US20090286781A1 - Use of Suluble Guanylate Cyclase Acitvators for Treating Acute and Chronic Lung Diseases - Google Patents

Use of Suluble Guanylate Cyclase Acitvators for Treating Acute and Chronic Lung Diseases Download PDF

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Publication number
US20090286781A1
US20090286781A1 US12/083,121 US8312106A US2009286781A1 US 20090286781 A1 US20090286781 A1 US 20090286781A1 US 8312106 A US8312106 A US 8312106A US 2009286781 A1 US2009286781 A1 US 2009286781A1
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Prior art keywords
acute
treatment
compounds
respiratory distress
medicament
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Abandoned
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US12/083,121
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English (en)
Inventor
Thomas Krahn
Johannes-Peter Stasch
Gerrit Weimann
Wolfgang Thielemann
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Bayer Pharma AG
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Bayer Healthcare AG
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Assigned to BAYER HEALTHCARE AG reassignment BAYER HEALTHCARE AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: THIELEMANN, WOLFGANG, KRAHN, THOMAS, STASCH, JOHANNES-PETER, WEIMANN, GERRIT
Publication of US20090286781A1 publication Critical patent/US20090286781A1/en
Assigned to BAYER SCHERING PHARMA AKTIENGESELLSCHAFT reassignment BAYER SCHERING PHARMA AKTIENGESELLSCHAFT MERGER (SEE DOCUMENT FOR DETAILS). Assignors: BAYER HEALTHCARE AG
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to the use of compounds of the formulae I-VI for manufacturing a pharmaceutical for the treatment of acute and chronic lung disorders such as the respiratory distress syndromes [acute lung injury (ALI), acute respiratory distress syndrome (ARDS)] and the treatment of COPD.
  • ALI acute lung injury
  • ARDS acute respiratory distress syndrome
  • Various noxae which directly damage the lung may induce an ALI or ARDS.
  • the term used is ALI when the PaO 2 /FiO 2 ratio is ⁇ 300 and is ARDS when the PaO 2 /FiO 2 ratio is ⁇ 200.
  • the mortality associated therewith is reported to be above 50% and thus represents a serious intensive care syndrome.
  • the pathophysiological findings are diffuse alveolar damage with invasion by neutrophils, macrophages, erythrocytes, development of hyaline membranes, emergence of protein-rich edema fluid, and loss of integrity of the alveolar epithelial barrier with pathologically increased permeability. Histology reveals after the stage of pulmonary edema formation an acute and chronic inflammatory reaction with a possible transition to fibrosis.
  • the main clinical feature is a drastic deterioration in gas exchange with reduced oxygenation and impeded ventilation through an impaired ventilation-perfusion distribution.
  • ALI/ARDS patients additionally show moderately severe pulmonary hypertension with increased pulmonary resistance, the causes being a hypoxic vasoconstriction and a destruction and obstruction of the pulmonary vascular endothelium. In some ALI/ARDS patients, this may lead to right heart failure.
  • cyclic guanosine monophosphate cGMP
  • NO nitric oxide
  • GTP guanosine triphosphate
  • the soluble guanylate cyclases consist of two subunits and very probably contain one heme per heterodimer, which is part of the regulatory center. This has a central importance for the mechanism of activation. NO is able to bind to the iron atom of the heme and thus distinctly increase the activity of the enzyme. Heme-free preparations by contrast cannot be stimulated by NO. CO is also able to attach to the central iron atom of heme, but the stimulation by CO is distinctly less than that by NO.
  • guanylate cyclase plays a crucial part in various physiological processes.
  • the activators according to the invention of soluble guanylate cyclase listed below, compounds I-VI are particularly suitable for producing pharmaceutical substances/medicaments for reducing pulmonary hypertension.
  • the compounds of the invention of the formulae I to VI have improved pharmacodynamic properties: on the one hand they act independently of NO produced endogenously in the pulmonary circulation, even if there is severe endothelial damage and the disease is at an advanced stage, to lower the pressure in the pulmonary arterial circulation.
  • the stimulators of soluble guanylate cyclase enhance the effect of endogenously produced NO and, in this way, improve the gas exchange through a selective pulmonary vasodilatation of the ventilated areas, leading to a reduction in the intrapulmonary shunt with an increase in oxygenation.
  • Clinical signs are cough and expectoration for at least 3 months a year in at least two consecutive years.
  • dyspnea occurs, initially during exercise, and later also at rest.
  • Partial respiratory insufficiency is present, with an increase in the carbon dioxide concentration in the blood and later a global insufficiency with additional decline in the arterial oxygen concentration.
  • Chronic hypoxia, inflammatory stimuli through nicotine and frequent bacterial exacerbations, and hyperinflation and overdistension of the airways through obstruction result in pulmonary vascular remodeling in COPD with intimal hyperplasia and medial hypertrophy.
  • average pulmonary arterial pressures above 40 mmHg are not uncommon, especially in patients with at least one episode of acute pulmonary failure. This is followed by chronic right-heart strain with the development of ankle edemas and chronic liver congestion, and an increasing deterioration in exercise capacity.
  • bronchodilatators ⁇ -mimetics, anticholinergics, methylxanthines
  • inhaled glucocorticoids to reduce the frequency of exacerbation and antibiotics in the case of bacterial bronchitis and pneumonias.
  • the chronic progression of the disorder cannot be substantially influenced by any of the established therapy principles.
  • Long-term oxygen therapy is recommended if there is global respiratory insufficiency with p A O 2 below 55 mmHg. Applied consistently, this therapy improves the prognosis but cannot influence the remodeling of all the layers of the pulmonary arterial vessel walls.
  • the activators according to the invention of soluble guanylate cyclase listed below, compounds I-VI are particularly suitable for producing pharmaceutical substances/medicaments for reducing pulmonary hypertension.
  • the compounds of the invention of the formulae I to VI have improved pharmacodynamic properties: on the one hand they act independently of NO produced endogenously in the pulmonary circulation, even if there is severe endothelial damage and the disease is at an advanced stage, to lower the pressure in the pulmonary arterial circulation.
  • the stimulators of soluble guanylate cyclase enhance the effect of endogenously produced NO and, in this way, improve the gas exchange through a selective pulmonary vasodilatation of the ventilated areas, leading to a reduction in the intrapulmonary shunt with an increase in oxygenation.
  • the present invention relates to the use of compounds of the formulae (I-VI) and the salts, hydrates, hydrates of the salts thereof for the manufacture of a medicament for reducing pulmonary hypertension.
  • the present invention further relates to the use of compounds of the formulae (I-VI) and the salts, hydrates, hydrates of the salts thereof for the manufacture of a medicament for the treatment of acute and chronic lung disorders such as respiratory distress syndromes [acute lung injury (ALI), acute respiratory distress syndrome (ARDS)] and the treatment of COPD.
  • acute and chronic lung disorders such as respiratory distress syndromes [acute lung injury (ALI), acute respiratory distress syndrome (ARDS)] and the treatment of COPD.
  • An additional exemplary embodiment of the present invention includes the procedure for the prophylaxis and/or for reducing pulmonary hypertension by use of at least one of the compounds of the formulae (I-VI).
  • the present invention further relates to pharmaceuticals comprising at least one compound of the invention and at least one or more further active ingredients, especially for the treatment and/or prophylaxis of the aforementioned disorders.
  • the compounds of the invention may have systemic and/or local effects. They can for this purpose be administered in a suitable way, such as, for example, by the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival or optic route or as implant or stent.
  • the compounds of the invention can be administered in suitable administration forms for these administration routes.
  • Administration forms suitable for oral administration are those which function according to the state of the art and deliver the compounds of the invention in a rapid and/or modified way, and which contain the compounds of the invention in crystalline and/or amorphized and/or dissolved form, such as, for example, tablets (uncoated or coated tablets, for example with coatings which are resistant to gastric juice or dissolve slowly or are insoluble and which control the release of the compound of the invention), tablets which rapidly disintegrate in the mouth, or films/wafers, films/lyophilizates, capsules (for example hard or soft gelatin capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • tablets uncoated or coated tablets, for example with coatings which are resistant to gastric juice or dissolve slowly or are insoluble and which control the release of the compound of the invention
  • tablets which rapidly disintegrate in the mouth or films/wafers, films/lyophilizates
  • capsules for example hard or soft gelatin capsules
  • Parenteral administration can take place with avoidance of an absorption step (e.g. intravenous, intraarterial, intracardiac, intraspinal or intralumbar) or with inclusion of an absorption (e.g. intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal).
  • Administration forms suitable for parenteral administration are, inter alia, injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilizates or sterile powders.
  • Examples suitable for other administration routes are medicinal forms for inhalation (inter alia powder inhalers, nebulizers), nasal drops, solutions, sprays; tablets for lingual, sublingual or buccal administration, films/wafers or capsules, suppositories, preparations for the ears or eyes, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milk, pastes, foams, dusting powders, implants or stents.
  • inhalation inter alia powder inhalers, nebulizers
  • nasal drops solutions, sprays
  • tablets for lingual, sublingual or buccal administration films/wafers or capsules, suppositories, preparations for the ears or eyes, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (such as, for example
  • the compounds of the invention can be converted into the stated administration forms. This can take place in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable excipients.
  • excipients include, inter alia, carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitan oleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (e.g. anti-oxidants such as, for example, ascorbic acid), colors (e.g. inorganic pigments such as, for example, iron oxides) and masking tastes and/or odors.
  • carriers for example microcrystalline cellulose, lactose, mannitol
  • solvents e.g. liquid polyethylene glycols
  • the present invention further relates to pharmaceuticals which comprise at least one compound of the invention of the formulae (I-IV), normally together with one or more inert, non-toxic, pharmaceutically suitable excipients, and to the use thereof for the aforementioned purposes.
  • the formulations can moreover comprise, appropriate for the intervention, active substance between 0.1 and 99% active ingredient, in a suitable manner 25-95% in the case of tablets and capsules and 1-50% in the case of liquid formulations, i.e. the active ingredient should be present in amounts sufficient to achieve the stated dose range.
  • mice were treated for 10 days with 300 ppm of compound (IV) in the feed. At the end of the test, the mice were sacrificed and the lungs were isolated. Histological workup and evaluation was carried out as in the abovementioned publication. Compared with the hypoxia control animals, the non-muscularized and partly muscularized fraction of the pulmonary vessels is significantly reduced in the mice treated with compound (IV) ( FIG. 1 ).

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  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)
US12/083,121 2005-10-06 2006-09-23 Use of Suluble Guanylate Cyclase Acitvators for Treating Acute and Chronic Lung Diseases Abandoned US20090286781A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE102005047946.4 2005-10-06
DE102005047946A DE102005047946A1 (de) 2005-10-06 2005-10-06 Verwendung von Aktivatoren der löslichen Guanylatzyklase zur Behandlung von akuten und chronischen Lungenkrankheiten
PCT/EP2006/009264 WO2007039155A2 (de) 2005-10-06 2006-09-23 Verwendung von aktivatoren der löslichen guanylatzyklase zur behandlung von akuten und chronischen lungenkrankheiten

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US20090286781A1 true US20090286781A1 (en) 2009-11-19

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US (1) US20090286781A1 (ja)
EP (1) EP1945218A2 (ja)
JP (1) JP2009510142A (ja)
KR (1) KR20080065283A (ja)
CN (1) CN101282727A (ja)
AU (1) AU2006299149A1 (ja)
BR (1) BRPI0616921A2 (ja)
CA (1) CA2624716A1 (ja)
DE (1) DE102005047946A1 (ja)
IL (1) IL190619A0 (ja)
RU (1) RU2417083C2 (ja)
WO (1) WO2007039155A2 (ja)
ZA (1) ZA200802874B (ja)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130035340A1 (en) * 2010-02-05 2013-02-07 Bayer Intellectual Property Gmbh sGC STIMULATORS OR sGC ACTIVATORS ALONE AND IN COMBINATION WITH PDE5 INHBITORS FOR THE TREATMENT OF CYSTIC FIBROSIS
US10265314B2 (en) 2013-07-25 2019-04-23 Bayer Pharma Aktiengesellschaft SGC stimulators in combination with additional treatment for the therapy of cystic fibrosis

Families Citing this family (6)

* Cited by examiner, † Cited by third party
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DE202008014557U1 (de) 2008-10-27 2009-03-12 Eberhard-Karls-Universität Tübingen Universitätsklinikum Therapeutische Verwendung
US20130158028A1 (en) * 2010-06-25 2013-06-20 Bayer Intellectual Property Gmbh Use of stimulators and activators of soluble guanylate cyclase for treating sickle-cell anemia and conserving blood substitutes
CN102485724B (zh) * 2010-12-06 2015-08-12 中国人民解放军军事医学科学院毒物药物研究所 取代噻吩基吡唑并吡啶类化合物及其医药用途
US9090610B2 (en) * 2011-04-21 2015-07-28 Bayer Intellectual Property Gmbh Fluoroalkyl-substituted pyrazolopyridines and use thereof
EP2875003B1 (de) * 2012-07-20 2016-11-16 Bayer Pharma Aktiengesellschaft Neue 5-aminotetrahydrochinolin-2-carbonsäuren und ihre verwendung
CN108785309A (zh) * 2018-04-23 2018-11-13 周静 化合物在制备治疗慢性肺病的药物中的用途

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US6693102B2 (en) * 2000-11-22 2004-02-17 Bayer Aktiengesellschaft Pyridine-substituted pyrazolopyridine derivatives
US6743798B1 (en) * 1998-07-29 2004-06-01 Bayer Aktiengesellschaft Substituted pyrazole derivatives condensed with six-membered heterocyclic rings
US20050089473A1 (en) * 2003-09-10 2005-04-28 Cedars-Sinai Medical Center Potassium channel mediated delivery of agents through the blood-brain barrier
US20050181066A1 (en) * 2002-04-26 2005-08-18 Altana Pharma Ag Novel use of guanylate cyclase activators for the treatment of respiratory insufficiency
US7087644B1 (en) * 1999-09-13 2006-08-08 Bayer Aktiengesellschaft Derivatives of dicarboxylic acid having pharmaceutical properties
US7173037B2 (en) * 2002-05-08 2007-02-06 Bayer Healthcare Ag Carbamate-substituted pyrazolopyridines
US20070225299A1 (en) * 2003-11-06 2007-09-27 Bayer Healthcare Ag Novel Combination Containing a Stimulator of Soluble Guanylate Cyclase and a Lipid-Lowering Substance

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GB2395431A (en) * 2002-11-20 2004-05-26 Northwick Park Inst For Medica Combination of a metal carbonyl compound and a guanylate cyclase stimulant or stabilizer for the therapeutic delivery of carbon monoxide
CA2534415A1 (en) * 2003-08-04 2005-02-17 Northwick Park Institute For Medical Research Therapeutic delivery of carbon monoxide
GB0325291D0 (en) * 2003-10-29 2003-12-03 Pfizer Ltd Novel combination
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US20080138444A1 (en) * 2004-10-05 2008-06-12 Bayer Healthcare Ag Method For Treating Bronchoconstriction and Pulmonary Vaso-Constriction

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US6743798B1 (en) * 1998-07-29 2004-06-01 Bayer Aktiengesellschaft Substituted pyrazole derivatives condensed with six-membered heterocyclic rings
US7087644B1 (en) * 1999-09-13 2006-08-08 Bayer Aktiengesellschaft Derivatives of dicarboxylic acid having pharmaceutical properties
US6693102B2 (en) * 2000-11-22 2004-02-17 Bayer Aktiengesellschaft Pyridine-substituted pyrazolopyridine derivatives
US20050181066A1 (en) * 2002-04-26 2005-08-18 Altana Pharma Ag Novel use of guanylate cyclase activators for the treatment of respiratory insufficiency
US7173037B2 (en) * 2002-05-08 2007-02-06 Bayer Healthcare Ag Carbamate-substituted pyrazolopyridines
US20050089473A1 (en) * 2003-09-10 2005-04-28 Cedars-Sinai Medical Center Potassium channel mediated delivery of agents through the blood-brain barrier
US20070225299A1 (en) * 2003-11-06 2007-09-27 Bayer Healthcare Ag Novel Combination Containing a Stimulator of Soluble Guanylate Cyclase and a Lipid-Lowering Substance

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130035340A1 (en) * 2010-02-05 2013-02-07 Bayer Intellectual Property Gmbh sGC STIMULATORS OR sGC ACTIVATORS ALONE AND IN COMBINATION WITH PDE5 INHBITORS FOR THE TREATMENT OF CYSTIC FIBROSIS
US10265314B2 (en) 2013-07-25 2019-04-23 Bayer Pharma Aktiengesellschaft SGC stimulators in combination with additional treatment for the therapy of cystic fibrosis

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ZA200802874B (en) 2009-09-30
KR20080065283A (ko) 2008-07-11
IL190619A0 (en) 2008-12-29
DE102005047946A1 (de) 2007-05-03
CN101282727A (zh) 2008-10-08
WO2007039155A3 (de) 2007-10-11
EP1945218A2 (de) 2008-07-23
RU2417083C2 (ru) 2011-04-27
WO2007039155A2 (de) 2007-04-12
CA2624716A1 (en) 2007-04-12
JP2009510142A (ja) 2009-03-12
BRPI0616921A2 (pt) 2011-07-05
RU2008117303A (ru) 2009-11-20
AU2006299149A1 (en) 2007-04-12

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